Researchers find three distinct immune responses for sicker COVID-19
patients
New immune profiles could help predict disease and guide treatments,
studies suggest

Date:
July 15, 2020
Source:
University of Pennsylvania School of Medicine
Summary:
Researchers have discovered three distinct immune responses to
the SARS- CoV2 infection that could help predict the trajectory
of disease in severe COVID-19 patients and may ultimately inform
how to best treat them. A second study uncovered new details about
the innate, or initial, response to SARS-CoV2.



FULL STORY ========================================================================== Researchers from the Penn Institute of Immunology discovered three
distinct immune responses to the SARS-CoV2 infection that could help
predict the trajectory of disease in severe COVID-19 patients and may ultimately inform how to best treat them.


==========================================================================
The findings were published in Science.

"For patients who are hospitalized with COVID-19, there isn't just one
way for the immune system to respond. There's a lot of heterogeneity,
which we've distilled down into what we're calling three "immunotypes,"
said senior author E. John Wherry, PhD, chair of the department of
Systems Pharmacology and Translational Therapeutics and director of
the Penn Institute of Immunology in the Perelman School of Medicine at
the University of Pennsylvania. "We're hopeful we may actually be able
to predict, or at least infer, the different immune patterns a patient
has based on clinical data. This would allow us to start thinking about enrolling patients to different types of clinical trials investigating treatments." The coronavirus triggers different immune responses and
symptoms in critically ill patients, but how those two correspond has
remained poorly understood, making treatment decisions more difficult.

While recent studies reveal details on the immune's response to the
virus, most have been single-case reports or focused on a small group
of individuals. This is the first study, to the author's knowledge, to
offer up a comprehensive immune profile of a large number of hospitalized patients.

The researchers applied deep immune profiling to capture individual
responses of 163 patients during the course of their infections. The
study included 90 hospitalized patients treated at the Hospital of the University of Pennsylvania, 29 non-hospitalized patients, and 44 healthy
donors with no COVID-19 infection. The immune responses varied among
the group, but there were patterns that hold clinical promise.



==========================================================================
The first immunotype had robust CD4+ T cell activity, with modest
activation of CD8+ T cells and peripheral blood lymphocytes. CD4+ and CD8+
act as the main inflammatory immune cells that work to clear viruses. The second immunotype was characterized mainly by a subset of CD8+ T cells
known as EM and EMRA and a modest activation of CD8+ T cells, memory
B cells, and peripheral blood lymphocytes. The third immunotype showed
little to no evidence of an immune response to the infection.

Next, researchers combined the profiling with clinical data to understand
the relationships between immune responses and disease. The first
immunotype was tied to more severe disease that included inflammation,
organ failure, and acute kidney disease. The second correlated not
with disease severity but instead pre-existing immunosuppression and
mortality. The third type, which had no immune activation, was not
associated with specific symptoms or clinical features, though they
varied.

The immunotypes developed by Wherry and team represent adaptive immune responses. A second study from researchers at Penn, published in Science Immunology, uncovered new details about the innate, or initial, response
to SARS-CoV2.

"T and B cell activity are informed by innate immune responses,"
said senior author Michael R. Betts, PhD, a professor of Microbiology
and program leader in the Penn Institute of Immunology, who is also a
co-author on the first study.

"We believe what's happening with the innate response of the immune system might be what's leading to these three immune phenotypes Dr. Wherry's lab identified." Profiling the blood samples of 42 infected patients (with moderate and severe disease) and 12 healthy donors, the researchers found
a similar heterogeneity in immune adaptive responses: robust activation
of CD4+ and CD8+ T cells, B cells, along with peripheral blood cells,
like neutrophils, monocytes, and "natural killer," or NK, cells.

While the innate responses were also heterogenous, the researchers
observed a decrease of CD15 and CD16 molecules on neutrophils and CD16
on NK cells, immature granulocytes, and monocytes, in patients with more
severe disease.

These two molecules are known players in the immune's response to viral infections that also represent a potential target for immunotherapy. How
they are driving and exacerbating the adaptive responses in the three immunotypes is an important question the labs are working to better
understand.

COVID-19 studies have been moving at an unprecedented speed as researchers
band together to find answers. Among its many efforts, Penn formed lab
and clinical research teams from diverse backgrounds to strengthen its
focus on the immune system, along with the COVID Processing Unit to
manage specimens to profile.

"Understanding the power of the immune system to regulate responses to
disease is one of the major advances in medicine in the last decade, and
Penn has been at the center leading that discovery. We are now applying
the broad expertise and experience of our more than 200-person immunology community toward the research and treatment of COVID-19," said Jonathan
A. Epstein, MD, executive vice dean, chief scientific officer, and a
professor of Cardiovascular Research at Penn. "The deep immuno-profiling
work the investigators applied here is likely to be useful not only now,
for this disease, but into the future for many others." The studies
were supported by the Penn Institute for Immunology Glick COVID-19
research award; the National Institute of Health (HL137006, HL137915, UM1- AI144288, P30-CA016520, AI105343, AI115712, AI117950, AI108545, AI082630, CA210944, CA230157); Mentored Clinical Scientist Career Development
Award from the National Institute of Allergy and Infectious Diseases
(K08 AI136660); Athersys, Inc, Biomarck Inc, and the Marcus Foundation
for Research; the Parker Institute for Cancer Immunotherapy; the Allen Institute for Immunology.


========================================================================== Story Source: Materials provided by University_of_Pennsylvania_School_of_Medicine. Note: Content may be
edited for style and length.


========================================================================== Journal References:
1. Divij Mathew, Josephine R. Giles, Amy E. Baxter, Derek A. Oldridge,
Allison R. Greenplate, Jennifer E. Wu, Ce'cile Alanio, Leticia
Kuri- Cervantes, M. Betina Pampena, Kurt D'Andrea, Sasikanth Manne,
Zeyu Chen, Yinghui Jane Huang, John P. Reilly, Ariel R. Weisman,
Caroline A. G.

Ittner, Oliva Kuthuru, Jeanette Dougherty, Kito Nzingha, Nicholas
Han, Justin Kim, Ajinkya Pattekar, Eileen C. Goodwin, Elizabeth
M. Anderson, Madison E. Weirick, Sigrid Gouma, Claudia P. Arevalo,
Marcus J. Bolton, Fang Chen, Simon F. Lacey, Holly Ramage, Sara
Cherry, Scott E. Hensley, Sokratis A. Apostolidis, Alexander
C. Huang, Laura A. Vella, The UPenn COVID Processing Unit, Michael
R. Betts, Nuala J. Meyer, E. John Wherry.

Deep immune profiling of COVID-19 patients reveals distinct
immunotypes with therapeutic implications. Science, July 15, 2020;
DOI: 10.1126/ science.abc8511
2. Leticia Kuri-Cervantes, M. Betina Pampena, Wenzhao Meng, Aaron M.

Rosenfeld, Caroline A.G. Ittner, Ariel R. Weisman, Roseline
S. Agyekum, Divij Mathew, Amy E. Baxter, Laura A. Vella, Oliva
Kuthuru, Sokratis A.

Apostolidis, Luanne Bershaw, Jeanette Dougherty, Allison
R. Greenplate, Ajinkya Pattekar, Justin Kim, Nicholas Han, Sigrid
Gouma, Madison E.

Weirick, Claudia P. Arevalo, Marcus J. Bolton, Eileen C. Goodwin,
Elizabeth M. Anderson, Scott E. Hensley, Tiffanie K. Jones, Nilam S.

Mangalmurti, Eline T. Luning Prak, E. John Wherry, Nuala J. Meyer,
Michael R. Betts. Comprehensive mapping of immune perturbations
associated with severe COVID-19. Science Immunology, 2020; 5 (49):
eabd7114 DOI: 10.1126/sciimmunol.abd7114 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/07/200715142251.htm

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